This section of this Medications Development Unit (MDU) outlines phase ll screening studies for armacotherapy of cocaine use in methadone- maintained subjects with agents that act through GABAergic or lutamatergic mechanisms. These studies would be carried out in two parts, with GABAergic agents being tested in Years l-2, and glutamatergic agents in Years 3-5. Our group has a long history of completing pharmacotherapy trials in cocaine-using methadone subjects, and examples have included desipramine, mazindol, amantadine, bromocriptine and bupropion. Pre- clinical evidence indicates that GABA and glutamate systems can modulate dopamine reward pathways which are thought to underlie the addictive properties of cocaine, and agents which modulate GABA and glutamate systems can reduce the reinforcing properties of cocaine in animal models. The GABAergic agents chosen for these pilot studies are: l) the GABAB agonist baclofen; and 2) the selective GABA reuptake inhibitor tiagabine. The glutamatergic agents chosen for phase I studies are: l) the NMDA receptor antagonist acamprosate and 2) the pre~synaptic glutamate release inhibitor lamotrigine. A total of 60 subjects will be recruited into each study for a total of 120 subjects over the entire five year period. Subjects will be randomized to one of five cells: placebo or two different doses of either baclofen or tiagabine (Study 1) or acamprosate or lamotrigine (Study 2) for a total of 8 or 12 weeks of active treatment for GABAergic and glutamatergic agents respectively. At the end of the active trials, medications would be tapered over a two week period. Primary outcomes will be self-reported cocaine use, three times weekly urine toxicology for the cocaine metabolite benzoylecgonine and treatment retention. It is hoped that we will demonstrate the efficacy and safety one or more of these agents for cocaine use in opiate-maintained subjects, and if encouraging results are obtained, phase ll controlled studies would be planned with promising candidates identified from these phase ll screening trials.